DESCRIPTION: (Applicant's Description) The recent development of innovative multimodality therapy for patients with localized adenocarcinoma of the pancreas has dramatically improved local-regional disease control, yet resulted in only a modest improvement in overall survival due to the early development of metastatic disease (liver) in most patients. Unfortunately, conventional treatments for metastatic adenocarcinoma of the pancreas are largely ineffective. Therefore, future therapeutic strategies must be based on a greater understanding of the biology of metastasis. Angiogenesis is an essential step in the metastatic cascade, and preliminary results suggest that the pleuripotential transcription factor NF-kB plays a major role in regulating this process. NF-kB may be activated by a number of mechanisms, most notably through autocrine or paracrine stimulation by HGF/SF. Elevated levels of NF-kB may in turn increase expression of VEGF. Studies from this institution have demonstrated that VEGF expression correlates with both vessel counts and metastases in adenocarcinoma of the colon. Further, the involvement of NF-kB in the regulation of VEGF transcription is supported by the identification of an NF-kB binding site in the VEGF promoter. Therefore, the hypothesis is that overexpression of the VEGF gene, which can be induced by constitutive activation of NF-kB, may initiate angiogenesis in human adenocarcinoma of the pancreas. This research application seeks to characterize the regulation of angiogenic factor expression at a molecular level and to determine the clinical effect of inhibition of angiogenesis. The specific clinical and basic science goals of this application are designed to: 1) evaluate the patterns of disease progression and survival in patients with non-metastatic adenocarcinoma of the pancreas treated with the angiogenesis inhibitor TNP-470; 2) determine whether vessel counts and VEGF can be used as prognostic factors in human pancreatic cancer; 3) determine if the transcription factor NF-kB regulates VEGF gene expression and is associated with tumor progression and metastasis; 4) determine whether or not the biological effect and the phenotype elicited by HGF are dependent on activation of NF-kB transcription factors in human pancreatic cancer cell lines.